rs879254520
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000558518.6(LDLR):c.420G>C(p.Glu140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E140K) has been classified as Pathogenic.
Frequency
Consequence
ENST00000558518.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.420G>C | p.Glu140Asp | missense_variant | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.420G>C | p.Glu140Asp | missense_variant | 4/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 11, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 05, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 23, 2017 | This c.420G>C (p.Glu140Asp) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11754108, 20145306, 22698793, 23680767). A different variant at the same residue (p.Glu140Lys) has also been described in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 21722902, 23375686) The p.Glu140Asp variant occurs within the low-density lipoprotein receptor repeat class A domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.420G>C variant is not detected in the general population and glutamate at position 140 of the LDLR protein is highly evolutionarily conserved. The c.420G>C (p.Glu140Asp) variant in the LDLR gene is classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E119D; This variant is associated with the following publications: (PMID: 10081189, 11754108, 31447099, 29261184, 11524740, 17094996, 20145306, 22698793, 34037665, 32770674, 33489595, 33418990, 33740630) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | LDLR: PS4, PM1, PM2, PM5, PP4 - |
Familial hypercholesterolemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 29, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 140 of the LDLR protein (p.Glu140Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11754108, 17094996, 20145306). ClinVar contains an entry for this variant (Variation ID: 251216). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu140 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11668627, 21722902, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Homozygous familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 23, 2018 | The p.Glu140Asp variant in LDLR has been reported in the heterozygous state in at least 10 individuals with familial hypercholesterolemia (FH; Kuhrova 2002, Tosi 2007, Chmara 2010, Tichy 2012, Vandrovcova 2013, Duskova 2011). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 251216) and was absent in large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu140Asp variant may impact the protein. Additionally, different amino acid changes at this position have been reported in individuals with FH (Stenson 2017), including the p.Glu140Lys variant which has been classified as likely pathogenic by other clinical laboratories (ClinVar variation ID 251213), suggesting that changes at this amino acid position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu140Asp variant is likely pathogenic. ACMG/AMP applied: PS4_Moderate, PM5, PM2, PP3. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2024 | The p.E140D pathogenic mutation (also known as c.420G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 420. The glutamic acid at codon 140 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 3 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This variant has been reported in multiple individuals with familial hypercholesterolemia (FH) (Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11; Chmara M et al, J. Appl. Genet. 2010 ; 51(1):95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Internal structural analysis indicates that this alteration results in disruption of the structurally critical Ca-binding SDE motif (Fisher C et al. Mol. Cell, 2006 Apr;22:277-83; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at